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Claudio Isella and colleagues report an analysis of colorectal cancer (CRC) gene expression data from patient-derived xenografts, which they use to reconcile three commonly used CRC classification systems. They find that the stem/serrated/mesenchymal (SSM) transcriptional subtype of CRC, previously linked to poor prognosis, is driven by stromal cells rather than tumor cells. Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.

The effect of somatic genetic changes in colorectal cancer on sensitivity to anti-EGFR antibody therapy is analysed. Genomics of a cancer during targeted therapy Victor Velculescu and colleagues examine the effect of somatic genetic changes in colorectal cancer on sensitivity to a common targeted therapy. Exome sequencing, copy number and targeted analyses of tumour response to anti-EGFR antibody blockade identified mutations in ERBB2 , EGFR , FGFR1 , PDGFRA , and MAP2K1 as potential mechanisms of primary resistance to this therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. In addition to highlighting new mechanisms of responsiveness to anti-EGFR therapies, this work provides new avenues for intervention in the management of colorectal cancer. Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation 1 . Recent studies have identified alterations in KRAS 2 , 3 , 4 and other genes 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2 , EGFR , FGFR1 , PDGFRA , and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

Although intracorporeal anastomosis has been demonstrated to be safe and effective after right colectomy, limited data are available about its efficacy after left colectomy for colon cancer located in splenic flexure. A multi-institutional audit was designed, including 92 patients who underwent laparoscopic left colectomy with intracorporeal anastomosis (IA) compared with 89 matched patients who underwent a laparoscopic left colectomy with extracorporeal anastomosis (EA). There was no significant difference in terms of age, sex, BMI, and ASA score between the two groups. Post-surgical history and stage of disease according to AJCC/UICC TNM were also similar. IA and EA groups demonstrated similar oncologic radicality in terms of the number of lymph nodes harvested (18.5 ± 9 vs. 17.5 ± 8.4; p = 0.48). Recovery after surgery was also better in patients who underwent IA, as confirmed by the shorter time to flatus in the IA group (2.6 ± 1.1 days vs. 3.4 ± 1.2 days; p < 0.001) and higher post-operative pain expressed in the mean VAS Scale in the EA group (1.7 ± 2.1 vs. 3.5 ± 1.6; p < 0.001). Laparoscopic left colectomy with intracorporeal anastomosis was associated with a lower rate of post-operative complications (OR 6.7, 95% CI 2.2–20; p = 0.001). However, when stratifying according to Clavien classification, the difference was consistently confirmed for less severe (class I and II) complications (OR 7.6, 95% CI 2.5–23, p = 0.001) but not for class III, IV, and V complications (OR 1.8, 95% CI 0.1–16.9; p = 0.59). Our results were consistent to hypothesize that a complete laparoscopic approach could be considered a safe method to perform laparoscopic left colectomy with the advantage of a guaranteed faster recovery after surgery. Further randomized clinical trials are needed to obtain a more definitive conclusion.

Background Optimal margin width is uncertain because of conflicting results from recent studies using overall survival as the end-point. After recurrence, re-resection and aggressive chemotherapy heavily affect survival time; the potential confounding effect of such factors has not been investigated. Use of recurrence-free survival (RFS) may overcome this limitation. The aim of this study is to evaluate the impact of width of resection margin on RFS and site of recurrence after hepatic resection for colorectal metastases (CRM). Methods From a prospectively maintained institutional database (1/1999–12/2007) we identified 314 patients undergone hepatectomy for CRM (1/1999–12/2007) with detailed pathologic analysis of the surgical margin and complete follow-up imaging studies documenting disease status and site of recurrence, which was categorized as: resection margin (M arg ), other intra-hepatic ( other IH), lung (L) or other extra-hepatic ( other EH). Recurrence-free estimation was the survival end-point. Results Median follow-up was 56.5 months. Two hundred and fifteen patients (68.8%) recurred at 288 sites after a mean of 15.5 months. A positive resection margin was associated with an increased risk of M arg recurrence ( P  < 0.001). The presence of ≥2 metastases was the only factor increasing the risk of positive margins ( P  < 0.05). The width of the negative resection margin (≥1 cm versus >1 cm) was not a prognostic factor of worse RFS (30.2% versus 37.3%, P  = 0.6). Node status of the primary tumour, and size and number of CRM were independent predictors of RFS. Conclusions Tumour biology and not the width of the negative resection margin affect RFS.

Introduction In recent decades liver resection has become a safe procedure, mainly because of better patient selection. Despite this progress, however, outcomes of hepatectomy in cirrhotic patients with portal hypertension are still uncertain. The aim of this study was to elucidate early and long‐term outcomes of liver resection in these patients. Methods Between 1985 and 2003, a total of 245 cirrhotic patients underwent hepatectomy for HCC. Altogether, 217 patients were eligible for this analysis and were divided into two groups according to the presence of portal hypertension at the time of surgery: 99 patients with portal hypertension and 118 without it. Results Patients with portal hypertension had worse preoperative liver function (Child‐Pugh A class patients: 66.7% vs. 94.9%; P < 0.0001). No differences were encountered in terms of intraoperative and pathology data. Operative mortality was similar (11.1% vs. 5.1%; P = 0.100), but patients with portal hypertension had higher morbidity (43.4% vs. 30.5%; P = 0.049) and received a higher rate of blood and plasma transfusions (51.5% vs. 32.2%, P = 0.004; 77.8% vs. 57.6%, P = 0.0017). Considering only Child‐Pugh A patients, short‐term results were similar in the two groups in terms of mortality, morbidity, and transfusion rates. The 5‐year survival rate was significantly higher in patients without portal hypertension (39.8% vs. 28.9%; P = 0.020), although when considering only Child‐Pugh A patients no difference of survival was encountered. Multivariate analysis identified Child‐Pugh classification, tumor diameter, and vascular invasion as independent predicting factors for survival. Conclusions Portal hypertension should not be considered an absolute contraindication to hepatectomy in cirrhotic patients. Child‐Pugh A patients with portal hypertension have short‐ and long‐term results similar to patients with normal portal pressure.

Background Fluorescence-guided visualization is a recently proposed technology in colorectal surgery. Possible uses include evaluating perfusion, navigating lymph nodes and searching for hepatic metastases and peritoneal spread. Despite the absence of high-level evidence, this technique has gained considerable popularity among colorectal surgeons due to its significant reliability, safety, ease of use and relatively low cost. However, the actual use of this technique in daily clinical practice has not been reported to date. Methods This survey was conducted on April 2020 among 44 centers dealing with colorectal diseases and participating in the Italian ColoRectal Anastomotic Leakage (iCral) study group. Surgeons were approximately equally divided based on geographical criteria from multiple Italian regions, with a large proportion based in public (89.1%) and nonacademic (75.7%) centers. They were invited to answer an online survey to snapshot their current behaviors regarding the use of fluorescence-guided visualization in colorectal surgery. Questions regarding technological availability, indications and techniques, personal approaches and feelings were collected in a 23-item questionnaire. Results Questionnaire replies were received from 37 institutions and partially answered by 8, as this latter group of centers do not implement fluorescence technology (21.6%). Out of the remaining 29 centers (78,4%), fluorescence is utilized in all laparoscopic colorectal resections by 72.4% of surgeons and only for selected cases by the remaining 27.6%, while 62.1% of respondents do not use fluorescence in open surgery (unless the perfusion is macroscopically uncertain with the naked eye, in which case 41.4% of them do). The survey also suggests that there is no agreement on dilution, dosing and timing, as many different practices are adopted based on personal judgment. Only approximately half of the surgeons reported a reduced leak rate with fluorescence perfusion assessment, but 65.5% of them strongly believe that this technique will become a minimum requirement for colorectal surgery in the future. Conclusion The survey confirms that fluorescence is becoming a widely used technique in colorectal surgery. However, both the indications and methods still vary considerably; furthermore, the surgeons' perceptions of the results are insufficient to consider this technology essential. This survey emphasizes the need for further research to reach recommendations based on solid scientific evidence.

The most accepted treatment for locally advanced pancreatic cancer is chemoradiotherapy. However, indications to and results of pancreatic resections after chemoradiation are not yet defined. From June 1999 to December 2003, 28 patients with locally advanced pancreatic cancer (group 1) were enrolled for institutional trials of gemcitabine-based chemoradiotherapy. Tumors were stratified as unresectable or borderline resectable according to the pattern of vascular involvement at pretreatment computed tomographic scan. Patients with partial response or stable disease and in-range Ca19-9 were surgically explored. Perioperative outcome and survival of group 1 were compared with 44 patients primary resected for localized cancer with or without adjuvant treatment in the same time period (group 2). Only one unresectable tumor was successfully resected compared to 7 out of 18 (39%) that were borderline resectable. Operations after chemoradiation were 1 hour longer and postoperative stays 5 days longer, but transfusion rate, morbidity, and mortality were not significantly different. Median survival was 15.4 months for group 1 (>21 for resected vs. 10 for not resected, P < 0.01) and 14 months for group 2. In both groups, a disease-free survival beyond 24 months was recorded only among patients resected with negative margins. The conversion of an unresectable cancer to a resectable one is a rare event. On the contrary, the resection of a borderline resectable tumor was successfully accomplished in one-third of cases. Chemoradiotherapy did not increase the operative risk, but the interventions were more technically demanding and required a longer postoperative stay. Patients resected after chemoradiation for a locally advanced tumor had at least the same survival as those primary resected for a localized one. Only R0 resections in both groups gave the chance of disease-free survival longer than 24 months.

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

Homing of colorectal cancer (CRC) cells to the liver is a non‐random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis‐specific peptide ligand (CGIYRLRSC) that binds a complex of E‐cadherin and α 6 integrin on the surface of CRC cells. We identify angiopoietin‐like 6 protein as a peptide‐mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin‐like 6 and tumoural α 6 integrin/E‐cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α 6 integrin and E‐cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.

Aim. To evaluate the impact of open or laparoscopic rectal surgery on pulmonary complications in elderly (>75 years old) patients. Methods. Data from consecutive patients who underwent elective laparoscopic or open rectal surgery for cancer were collected prospectively from 3 institutions. Pulmonary complications were defined according to the ACS/NSQUIP definition. Results. A total of 477 patients (laparoscopic group: 242, open group: 235) were included in the analysis. Postoperative pulmonary complications were significantly more common after open surgery (8 out of 242 patients (3.3%) versus 23 out of 235 patients (9.8%); p=0.005). In addition, PPC occurrence was associated with the increasing of postoperative pain (5.04 ± 1.62 versus 5.03 ± 1.58; p=0.001) and the increasing of operative time (270.06 ± 51.49 versus 237.37 ± 65.97; p=0.001). Conclusion. Our results are encouraging to consider laparoscopic surgery a safety and effective way to treat rectal cancer in elderly patients, highlighting that laparoscopic surgery reduces the occurrence of postoperative pulmonary complications.